This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Peripheral Arterial Disease (PAD) affects approximately 9 million individuals in the US and is associated with significant morbidity and mortality. Symptoms of PAD are related to insufficient arterial blood flow, which results in exercise-induced ischemic pain (claudication) Supervised exercise training, particularly treadmill training, is recognized as an effective intervention to improve walking distance in this population. One study has demonstrated that aerobic arm training alone improved walking distance in patients with claudication. This proposal builds on an ongoing study (ETC-I) assessing the relative effects of a 12-week program of upper body versus lower body aerobic training (either alone or in combination) on exercise capacity and functional status in patients with lifestyle limiting claudication. The primary outcomes for that study are essentially clinical in nature (changes in walking distance and functional status). Preliminary data indicate that subjects performing upper body aerobic training are demonstrating substantial improvement in walking ability, similar to those performing lower body aerobic training. This finding suggests a systemic as opposed to local mechanism of exercise-related improvement. The current study (ETC-II) will examine underlying physiological mechanisms to explain (and measure) the clinical changes currently being observed in our claudication subjects. It will include assessment of the effect of exercise on more basic physiological variables associated with endothelial injury and thrombosis/hemostasis. It will allow measurement of changes in these factors with exercise training and evaluation of differences between those engaging in upper body (non-ischemic) versus lower body (ischemic) exercise. This will provide evidence to tie the clinical outcomes seen with exercise training to physiologic mechanisms and provide direction for development of improved interventions in this population. Primary Objective: To determine the relative effects of a 12-week supervised program of treadmill exercise training or arm ergometry, alone or in combination, versus [unreadable]usual care[unreadable] in subjects with claudication on systemic physiologic measures associated with endothelial injury and thrombosis/hemostasis. The primary outcome is change in flow-mediated vasodilation (FMD) of the brachial artery. Hypotheses include: [unreadable] Both upper and lower extremity training will result in improvement in (FMD), as well as improvements in systemic markers of endothelial injury and thrombosis/hemostasis, when compared with control subjects receiving [unreadable]usual care[unreadable]. [unreadable] Exercise-induced improvements in maximal walking distance will be positively related to changes in these systemic physiologic measures. Secondary Objective: To determine which physiological markers are most appropriate for inclusion in a subsequent clinical trial and to gather preliminary data that determines effect sizes, thus allowing power calculations for subsequent investigations. Methods: Patients will undergo screening including medical history, measurement of the ankle brachial index (ABI), and a cardiopulmonary exercise test. Subjects who meet inclusion/exclusion criteria will be evaluated in the GCRC on two separate days. These evaluations include blood sampling before and after a symptom-limited graded treadmill test and evaluation of vascular function. Following completion of all screening procedures, subjects will be randomly assigned to one of 4 groups: (1) Control, (2) Treadmill Walking, (3) Arm Ergometry, or (4) Combined Arm Ergometry and Treadmill Walking for a 12 week study period. Exercise subjects perform 60 minutes of supervised exercise in the exercise laboratory 3 times per week for 12 weeks. Control subjects continue "usual care" and report to the exercise laboratory once a week for vital sign evaluation and encouragement. All measurements will be repeated within 1 week of completion of the exercise program.